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Terri DeFrancesco, DVM, DACVIM (Cardiology), DACVECCNorth Carolina State UniversityCollege of Veterinary Medicine
• Spironolactone/hydrochlorthiazide(Aldactazide®)– Will add in with end‐stage refractory HF
Spironolactone (Aldactone)
• Competitive antagonist of aldosterone
• Potassium sparing diuretic
• Weak diuretic, synergism with furosemide
• Slow onset of action, peak in 48 ‐ 72 hours
• Dose: 2 mg/kg/day
• Adverse effect: Azotemia, hyperkalemia
Retention of NaLoss of K and MgSympathetic stimulationParasympathetic inhibitionMyocardial and vascular fibrosisBaroreceptor dysfunctionImpairs arterial compliance
Aldosterone promotes:Role of Aldosterone in HF
Aldosterone blockade:
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Vetmedin® (pimobendan)
Selective peripheral phosphodiesterase III inhibitor
• Dilates both arterial and venous vessels
• Reduces preload and afterload• Improves cardiac function
Calcium sensitizer Promotes efficient use of existing
calcium Increases force of contraction Does not increase myocardial
energy requirements
Balanced vasodilationDirect heart muscle action
Dual Mode of Action (“Inodilation”)
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Vetmedin®
Pharmacokinetics and Pharmacodynamics
• Rapid absorption
– Mean peak plasma levels achieved 0.5‐1.0 hour after administration of a single oral dose
• Pimobendan is oxidatively demethylated to an active metabolite (UD‐CG 212)
• Prolonged pharmacodynamic effect (>8h)• Routes of excretion
– Feces: 95%– Kidneys: 5%
Vetmedin®
Labeling
• Indications
– Management of the signs of mild, moderate, or severe (modified NYHA Class II, III, or IV) CHF in dogs due to ValvularInsufficiency (MVD) and Dilated Cardiomyopathy (DCM)
– Use with concurrent therapy for congestive heart failure (eg, furosemide, etc) as appropriate on a case‐by‐case basis
• Dose rate
– 0.23 mg/lb (0.5 mg/kg) per day, in two divided doses that are not necessarily equal
– Chewable 1.25, 2.5, 5 and 10 mg scored tablets
– Dose escalate for worsening HF –
• Can increase dose and frequency
Questions about using Pimobendan?
• When to add in pimobendan in dogs with HF secondary to MVD or DCM?
• Does one still use digoxin together with pimobendan?• Should one use pimobendan in dogs prior to the onset of HF?
• Can one or should one use pimobendan without an ACE inhibitor in a dog with HF?
• Are there other indications for pimobendan?– Cats with congestive heart failure?– Dogs with severe pulmonary hypertension (idiopathic or due to heartworm disease)?
– Dogs with other causes of HF, e.g., PDA or endocarditis?
• What are the adverse effects?
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JVIM 2008
When to add in pimobendan in dogs with HF secondary to MVD?
• First onset of heart failure*• Helpful in older dogs with concurrent renal insufficiency – allows lower furosemide dose and improves azotemia
• Will reduce the heart size in some dogs as seen by thoracic radiographs– Helpful for dogs with concurrent collapsing trachea and bronchi to reduce compression from left atrialenlargement
*Haggstrom, JVIM, 2008
March 2011 April 2012
9 yo MC Chihuahua5/6 systolic murmur PMI left apex
Occasional cough Frequent cough
Pimobendan: What are the adverse effects?
• Well tolerated drug
• Concerns about tachyarrhythmia
• May worsen MR if given too early
• NCSU Cardiology has used higher than recommended doses and frequencies with no adverse effects and improved clinical signs
Chetboul JVIM 2007
• Small prospective comparative study in dogs with asymptomatic MVD for 512 days (12 dogs)
Sildenafil: 1 – 2 mg/kg PO q 8 – 12 hr if pulmonary hypertension Amlodipine: 0.1‐0.2 mg/kg PO q 12 – 24 hr for additional vasodilation Diltiazem/digoxin: if A‐fib Periodic abdominocentesis for Right HF
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Terri DeFrancesco, DVM, DACVIM (Cardiology), DACVECCNorth Carolina State UniversityCollege of Veterinary Medicine
• 40% may not have murmur on initial ER examination
• Hypothermia + bradycardia are not uncommon
• Antecedent event is common
– Corticosteroids
– Boarding
– Vet visit
– Procedure Rush J Am Vet Med Assoc 2002
Corticosteroid‐associated HF in cats
• 11% of 271 cats with CHF received steroid within 90 days
• 28.8 odds ratio of long acting steroid inj. with HF (p < 0.005)
• Survivors had better median survival than other cats (439 d)
Smith ACVIM abst. 2002
Am J Vet Res2007
• Plasma volume ↑ by 13 % in 3 – 6 d. > 40 % in 3/12 cats
• Volume expansion as a result of an intra‐ to ‐ extracellular fluid shift secondary to glucocorticoid mediated extracellular hyperglycemia.
J Vet Radiol US 2013
1. Radiographic LA enlargement can be absent even in the presence of LAE enlargement on ECHO
2. PV enlargement is a poor indicator of left‐sided CHF in cats with PAs more often enlarged as compared to PV
3. Cardiomegaly is a consistent finding in cats with left‐sided CHF making radiographic assessment of heart size diagnostically more important than evaluation of left atrial size in cats with respiratory distress.
Focused ER Echocardiography
• 2D Helpful to distinguish HF from respiratory– Enlarged LA– Echo smoke – spontaneous echo – Pleural + pericardial effusion– Left ventricular hypertrophy– Right ventricular hypertrophy– Systolic function– Lung rockets
• Advanced echocardiographictechniques:– Pulmonary arterial pressure– Left ventricular filling pressures
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Enlarged Left Atrium
NTproBNP in dyspneic cats
On ROC analysis with a cutoff value >265 pmol/L
Sensitivity: 91%Specificity: 85 %for correctly identifying the cause of the breathlessness.
This box and whisker plot shows the results of a 12 center study evaluating the value of NTproBNP in correctly identifying the cause of dyspnea (breathlessness) in 139 cats. 85 cats had heart failure, 54 had respiratory disease.
Fox PR, et al. Comparison of NTproBNP concentration in cats with acute dyspnea from cardiac or respiratory disease J Vet Cardiol 2009.
The SNAP Feline proBNP Test had:
• 99.5% agreement with the Cardiopet proBNP Test when concentrations of NTproBNP were <100 pmol/L.
• 95.0% agreement with the Cardiopet proBNP Test when concentrations of NTproBNP were ≥270 pmol/L.
ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults
• “Concentrations of BNP or NT‐proBNP should be measured in patients being evaluated for dyspnea in which the contribution of HF is not known. Final diagnosis requires interpreting these results in the context of all available clinical data and ought not to be considered a stand alone test.” (Level of Evidence: A)
Circulation. 2009
Furosemide
Chronic Feline Heart Failure
Pimobendan
Diltiazem
Anti‐thromboticsClopidogrel
AspirinDalteparin (LMWH)
ACE‐InhibitorsEnalaprilBenazepril
Atenolol
Nutraceuticals
SpironolactoneSildenafilAmlodipine
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Kaplan‐Meier Survival Curve Showing Time to Failure or Death for Treatment Group
0%
20%
40%
60%
80%
100%
0 200 400 600 800 1000 1200
Enalapril (n=27)median, 920 d
Furosemide (n=31)median, 235 d
All Cardioactive Drugs (n=87) median, 227 d
Dilacor (n=31)median, 227 d
Atenolol (n=29)median, 72 d
All Cats (n=118)Entire Study Duration
Pro
port
ion
Sur
vivi
ng
Days from Randomization
Courtesy of Dr. Phil Fox ACVIM 2003
ACUTE (IN HOSPITAL) MANAGEMENT OF SEVERE HEART FAILURE
CAT Furosemide:1‐4 mg/kg IM or IV bolus +/‐ CRI (Max 12 mg/kg/day)
Oxygen Sedation:
Butorphanol 0.1‐0.2mg/kg IM (Minimize Stress!!!) Thoracocentesis: if pleural effusion Pimobendan: Especially if refractory, LV systolic
dysfunction or azotemia‐ 0.25 mg/kg PO BID (when able to swallow)
Nitroglycerin: ¼” transdermal q 8 – 24 hr for 1‐2 d or Nitroprusside: 0.5‐5 ug/kg/min IV (careful BP monitoring)
Puff: inhaled albuterol (2 puffs) or SQ terbutalline for peribronchiolar edema or refractory respiratory distress
Dobutamine: 1‐5 ug/kg/min IV (ECG monitoring)
Vetmedin® (pimobendan)
Selective peripheral phosphodiesterase III inhibitor
• Dilates both arterial and venous vessels
• Reduces preload and afterload• Improves cardiac function
Calcium sensitizer Promotes efficient use of existing
calcium Increases force of contraction Does not increase myocardial
energy requirements
Balanced vasodilationDirect heart muscle action
Dual Mode of Action (“Inodilation”)
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What about Pimobendan in cats with HF?
• Not labeled for use in cats
• Hypertrophic Cardiomyopathy is listed as a contra‐indication however….
• Use has evolved from severe end stage HF secondary to presumed remodeled HCM to most hospitalized HF cat
• Allows decrease furosemide dose in azotemia and decreased intervals of thoracocentesis
• SAME DOSE as DOG (0.5 mg/kg/day)
• Retrospective
• 16 cats each group:
• MST with Pimobendan = 49 d
• MST without Pimobendan = 12 d
NCSU Pimobendan Retrospective in Feline HF due to HCM or HOCM
• 2003 – 2013 NCSU
• Cats treated pimobendan– Within 48hrs of HF diagnosis
– FS of 30% or greater
– Received at least 2 doses of pimobendan prior to death
– Maintained the use of pimobendan from the time of inclusion to study end or death.
• Used in refractory HF (pl. eff, ascites) in addition to triple tx
• Concern with azotemia and ↑ K+
• 1 – 2 mg/kg once daily
• Smallest tablet = 25 mg
VASODILATORS IN HFAfterload and Cardiac Performance
Afterload
CardiacOutput
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ACE inhibitors in Feline HFEnalapril vs. Benazepril
• Benazepril
– Longer duration of action in cat = once daily dosing
– Route of excretion is 85% via the biliary system (50% in dogs) = safer with renal impairment
– Smallest tablet = 5 mg
SILDENAFIL(Viagra®, Revatio®)
• Phosphodiesterase V inhibitor that causes nitric oxide induced vasodilation
• Vascular bed selectivity• Used pulmonary hypertension in dogs• Anecdotal benefit in cats with severe refractory pleural effusion (in addition to triple tx)